Journal
CELL RESEARCH
Volume 26, Issue 6, Pages 728-742Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2016.48
Keywords
MeCP2; cholinergic system; Rett syndrome; RTT-like phenotypes
Categories
Funding
- National Natural Science Foundation of China for Distinguished Young Scientists [81225007]
- National Natural Science Foundation of China [31430034, 91432306]
- Funds for Creative Research Groups of China [81221003]
- Program for Changjiang Scholars and Innovative Research Team in University
- Fundamental Research Funds for the Central Universities
- Zhejiang Province Program for Cultivation of High-level Health Talents
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Mutations in the X-linked MECP2 gene cause Rett syndrome (RTT), an autism spectrum disorder characterized by impaired social interactions, motor abnormalities, cognitive defects and a high risk of epilepsy. Here, we showed that conditional deletion of Mecp2 in cholinergic neurons caused part of RTT-like phenotypes, which could be rescued by re-expressing Mecp2 in the basal forebrain (BF) cholinergic neurons rather than in the caudate putamen of conditional knockout (Chat-Mecp2(-/y)) mice. We found that choline acetyltransferase expression was decreased in the BF and that alpha 7 nicotine acetylcholine receptor signaling was strongly impaired in the hippocampus of Chat-Mecp2(-/y) mice, which is sufficient to produce neuronal hyperexcitation and increase seizure susceptibility. Application of PNU282987 or nicotine in the hippocampus rescued these phenotypes in Chat-Mecp2(-/y) mice. Taken together, our findings suggest that MeCP2 is critical for normal function of cholinergic neurons and dysfunction of cholinergic neurons can contribute to numerous neuropsychiatric phenotypes.
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